Identification of a postmortem redistribution factor (F) for forensic toxicology

Abstract

Background

Postmortem redistribution (PMR) refers to the changes that may occur in drug concentrations after death. Consequently, postmortem concentrations in blood may not always replicate the antemortem drug levels. Literature supports the model describing drugs with a liver (L) concentration to peripheral blood (P) concentration ratio less than 5 (L/kg) being prone to little or no PMR. Conversely, drugs with a L/P ratio greater than 20 to 30 (L/kg) have propensity for substantial PMR.

Findings

Expanding upon this prior work, the current paper presents the concept of a postmortem redistribution factor (F) for a drug, which characterizes the direct relationship between postmortem peripheral blood and the corresponding antemortem whole blood concentration.

Conclusions

Development of the concept of a "postmortem redistribution factor" will provide a more definitive and authoritative drug ranking, and possibly, numerical interpretation of PMR for forensic toxicologists.

Findings

Introduction

A potentially significant issue complicating interpretation of postmortem drug concentrations results from the phenomenon referred to as postmortem redistribution (PMR). Postmortem drug concentrations in the blood may not always straightforwardly parallel antemortem drug concentrations in the blood due to the movement of the drugs after death. Accordingly, some authors have argued a cautious approach in interpreting postmortem concentrations, and others have taken a far more pessimistic and even cynical perspective. The mechanisms involved in PMR are both complicated and poorly understood. However, postmortem drug concentrations in the blood may follow some commonly accepted trends that aid with interpretation. Generally, the characteristics of the drug itself can be used to predict if a drug is subject to PMR. Substantial changes in blood drug concentrations are predicted for basic, lipophilic drugs with a high volume of distribution (>3 L/kg) (Prouty & Anderson [1990]). When PMR occurs, blood specimens drawn from the central body cavity and heart generally exhibit higher drug concentrations postmortem than specimens drawn from peripheral areas, most commonly the femoral region. Diffusion of drugs from organ tissues into the blood may explain the observed phenomenon.

Previous attempts to assess and account for PMR have utilized postmortem blood specimens collected from at least two areas of the body at autopsy, a peripheral area and a central area (often the heart), so that a comparison could be made. The resulting postmortem blood ratio was considered to reflect a drug's potential for PMR (Prouty & Anderson [1990]; Dalpe-Scott et al. [1995]). Recent work, however, has described ambiguities with this approach (McIntyre et al. [2012]).

The collection, analysis, and comparison of antemortem blood specimens are obviously helpful in assisting with the interpretation of postmortem blood drug concentrations, but relevant specimens are only rarely available. In a set of case studies of six drugs, concentrations in the postmortem femoral blood specimens exceeded the antemortem concentrations in five of the drugs studied, suggesting that even peripheral blood exhibited redistribution (Cook et al. [2000]). The potential for redistribution of other drugs in postmortem peripheral blood has also been documented (Gerostamoulos et al. [2012]).

The liver (L) to peripheral blood (P) ratio has been proposed as a more dependable marker for PMR, with ratios less than 5 (L/kg) indicating little to no propensity towards PMR, and ratios exceeding 20 to 30 (L/kg) indicative of a propensity for substantial PMR (McIntyre et al. [2012]). A number of reports elaborating on, and supporting, this model have now been published (McIntyre & Mallett [2012]; McIntyre & Meyer Escott [2012]; McIntyre & Anderson [2012]; McIntyre et al. [2013a]; McIntyre et al. [2013b]). Furthermore, a direct correlation between the postmortem peripheral blood and corresponding antemortem concentration - by consideration of the L/P ratio - has been expressed (McIntyre et al. [2013c]). The report, describing methamphetamine cases, found that the postmortem peripheral blood concentrations were approximately 1.5 times higher than the corresponding concentrations attained in whole blood specimens collected before death. Given that the L/P ratios for methamphetamine had been confirmed to be approximately 6 (L/kg), it was then projected that drugs exhibiting L/P ratios between 5 and 10 (L/kg) would theoretically yield postmortem peripheral blood concentrations up to twice the corresponding antemortem concentrations - a measure of PMR potential. It was further hypothesized that L/P ratios ranging from 10 to 20 (L/kg) would demonstrate greater potential for PMR with postmortem peripheral blood concentrations 2 to 3 times that of the corresponding antemortem levels and consequently even higher L/P ratios indicative of even greater potential for PMR.

The current document sets out to expound upon this L/P model and its resultant implications by proposing the concept of a postmortem redistribution factor (F) for a drug. The postmortem redistribution factor has been defined as a factor that characterizes the direct relationship between a drug's postmortem peripheral blood and the corresponding antemortem (AM) whole blood concentration.

Hypothesis

Equation 1 presents the proposed relationship between the antemortem whole blood concentration of a compound and the corresponding postmortem peripheral blood concentration:

$$\mathbf{AM}\mathbf{=}\mathit{P}/\mathit{F}$$

(1)

where AM = antemortem whole blood concentration, P = postmortem peripheral blood concentration, and F = postmortem redistribution factor.

Rearrangement of Equation 1 gives

$$\mathit{F}\mathbf{=}\mathbf{P}/\mathbf{AM}$$

(2)

Thus, an example of an experimental (or actual) F could be determined for a drug where both the postmortem peripheral blood and antemortem whole blood drug concentrations have been determined in the same individual (assuming an insignificant delay between the collection of the antemortem blood and the time of death).

Discussion

Considering the methamphetamine data (McIntyre et al. [2013c]), an experimental (actual) F for methamphetamine of 1.5 is predicted - postmortem peripheral blood concentrations being 1.5 times (on average) greater than the corresponding antemortem concentrations.

A related approach to assess potential for PMR has also recently been described (Launiainen & Ojanpera [2013]). This study presented data for 129 drugs comparing postmortem femoral blood concentrations to therapeutic plasma concentrations to describe drugs' propensity for PMR. This study analyzed a large number of cases where median postmortem drug concentrations were compared with estimations of the therapeutic concentrations. These authors projected a similar ratio for methamphetamine of 1.8. Although these data represent a practical attempt to describe PMR, it is conceivable that the determination of an F value from analytically determined postmortem data (such as the unique drug L/P ratio) may well produce more consistently accurate estimates.

The principal goal of these endeavors was to attempt to develop a ranking of drugs and indicate their propensity for and, subsequently, their potential extent of PMR. Until now, most efforts in interpretation have simply described PMR by an aphorism, ranging from ‘the drug has not been found to exhibit PMR’ to ‘the drug is subject to PMR.’ Such descriptions have never been particularly useful in the interpretation of postmortem drug concentrations, especially in relation to deducing what the drug concentration may have been at the time of death. The development of the concept of a systematically based postmortem redistribution factor will provide a more definitive and authoritative ranking and possibly numerical interpretation of PMR.